The hepatic receptor for asialoglycoproteins was found to be modulated by the glucose concentration in the medium of the human hepatoma cell line, HepG2. The surface binding of asialoorosomucoid increased from 20 ng/mg of cellular protein to about 40 ng/mg as the glucose concentration was increased from 10 to 50 mg %. Scatchard plot analysis indicated a rise in the number of binding sites as well as a two-fold increase in binding affinity. The binding of antibody against the human receptor did not change, confirming that the actual number of receptors remained constant in face of an increased number of binding sites. Specificity of the glucose effect was indicated by the binding of insulin and transferrin to their respective receptors, which was unaffected under the conditions that increased asialoglycoprotein binding. The up-modulating effect of glucose was abolished by 2-deoxyglucose, an inhibitor of glucose metabolism, and by cycloheximide, an inhibitor of protein synthesis. The mechanism responsible for the modulation is currently unknown, although presumptive evidence is available to suggest that it is mediated by changes in the level of cyclic GMP.